Rare diseases are chronic and sometimes life-threatening conditions which differ from others due to less definite identity and more difficult clinical management. These peculiar features may hinder the parental adaptational process. The study aimed to compare the emotional burden and coping strategies of parents of children with rare diseases (CRD) with those of parents of children with chronic diseases (CCD). Quality of life, anxiety, depression, and mood states of 55 parents of CRD and of 56 parents of CCD were assessed by specific validated assessment tools. Parametric and non-parametric tests were used for multiple comparisons. Bivariate correlations were employed to explore the relationship between coping and emotional burden. Parents of CRD were more anxious, more confused–bewildered, and less active–vigorous than those of CCD (p < 0.001). Parents of CCD preferentially used some problem-focused and emotion-focused strategies (active coping, seeking instrumental social support, and positive reinterpretation and growth), whereas parents of CRD more often turned to religious coping (p < 0.001). The indefinite and uncertain identity of rare diseases hindered the adaptational process and appeared to impede the use of active coping, seeking instrumental social support, and positive reinterpretation and growth, that was correlated to higher level of vigor–activity among parents of CCD (p < 0.001). Conversely, the falling back on religious coping by parents of CRD didn’t result in improvement of any burden features. The main findings of the present study seem to suggest that both parents of CRD and those of CCD achieved good overall adaptation 1 year after child’s illness diagnosis, but they did so in different ways, showing slightly differences in emotional burden, probably due to the lack of available medical knowledge about diagnosis, prognosis and treatment of rare diseases. Therefore these findings stress the relevance of physician training and of providing information in the field of rare diseases.